Natural Lovastatin (NL) as an Anticancer Agent: Docking and Experimental Studies

Abstract

Purpose: Lovastatin commonly used as a cholesterol-lowering agent due to its inhibitory action on HMG-CoA reductase enzyme. Lovastatin and other statins may reduce the development of melanomas. Our recent research showed that lovastatin can also be used as anticancer agent and especially naturally synthesized lovastatin has more effect on cancer inhibition over the chemically synthesized. Procedure: The present study was designed to test the anticancer activity of naturally extracted lovastatin against Dalton’s Ascites Lymphoma (DAL) cells. Molecular docking of Bax-Bcl-2 and caspase-3 proteins were interacted with lovastatin and 5-Fluorouracil (5-FU) ligands, followed by which different groups of animals were infected with DAL  cells and treated with natural and standard lovastatin which are then compared with control groups. Live and dead cells were differentiated by acridine orange/ethidium bromide dual staining, and DNA damage and organ toxicity were assessed through histopathology study. Finally, the expression level of apoptotic protein was done with Bcl-2, Bax, caspase-3 through immunoblot analysis. Results: The entire computational analysis provided the supportive evidence to confirm the natural lovastatin (NL) performing as an anticancer agent and agreed with the experimental results. Interestingly, the caspase-3 has best interaction with natural lovastatin when compared to standard anticancer drug 5-FU. Similarly, the Bax-Bcl-2 protein also has highest interaction with NL than the 5-FU. The cell viability was assessed using trypan blue staining, and the result revealed that the half of inhibitory concentration (IC₅₀) as 150 ppm, which was used as treatment dose for in vivo study. Upon the treatment, the decline of cancer by reduction of body weight, ascites fluid volume, and lengthening of life span were observed. The AO/EB staining clearly showed number of late apoptotic cells in NL and standard lovastatin treated groups, when compared with standard cancer drug (5-FU)-treated group. DNA damage showed clearly high level of DNA damage in animals treated with NL, natural lovastatin, which is evident for the progression of apoptosis. Further, the expression of apoptotic marker protein such as Bcl-2, Bax, and caspase-3 proved that the cancer cells upon treatment undergo cell death through apoptosis. The histopathology of treated and control groups showed that there is no adverse effect on vital organs like liver and kidney. Conclusion: Overall, the present study clearly showed the effective tumor-controlling property of naturally derived lovastatin. However, the detailed molecular investigation would be required to understand the molecular mechanism of action.